Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.

Source

Department of Internal Medicine, University of Texas Southwestern Medical Center, Touchstone Center for Diabetes Research, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Roger.Unger@utsouthwestern.edu

Abstract

Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.

PUBMED ARTICLE

Welcome to part II of my review! There will certainly be a part III and, depending on how long part III turns out to be, there will likely be a part IV to go over the intense diagrams of this paper. I’m also going to try something new with embedding mouse-over definitions for some of the super sciency vocabulary. This part of the paper was especially fascinating because it looks at obesity not from a disease point of view, but from a defense mechanism point of view. Adipocytes (or fat cells) are also shown in a completely new, and indeed heroic, light too. Get ready for some “Huh, I never thought of it that way!”

Is Metabolic Syndrome Part of Your Genetic Fate?

The short answer is – we don’t know. There are a number of candidate genes that might increase susceptibility to metabolic syndrome, many of which have to do with making sure excess calories are stored in the proper place (ie adipose tissue as opposed to on random organs).

Adipocytes (Fat Cells) – Most Helpful Little Guys Everyone Loves to Hate

Fat cells have it rough. They’re absolutely critical to the proper healthy function of everyone’s body, and yet they are demonized for doing a heck of a job under constant food mismanagement by the body’s owner. Most cells in the body are incapable of storing enough calories to sustain themselves for very long (called ‘lipid-intolerant nonadipose tissues’), and they rely on adipocytes to stockpile enough fuel for all the cells in case of starvation/famine. It’s a little like Aesop’s Fable of the grasshopper and the ant, except that no one dies of starvation. In addition to not being able to store many calories, most cells can’t handle too much fuel either, and the trusty adipocytes come to the rescue yet again, sucking up extra fuel so no one gets hurt.

These little fat cells do more than store fuel and distribute it in times of need – they’re also actively communicating with your brain. As adipocytes expand from taking in fuel, they secrete leptin. Leptin is a hormone that minimizes the amount of fats building up in non-adipocytes by inducing fatty acid oxidation. Fatty acid oxidation reduces free fatty acids into acetyl-coenzyme A, which can then be used in a cell’s metabolic cycle. Leptin also acts on the hypothalamus in the brain to curb appetite, which is your fat cells’ way of shouting:

HEY, WE’RE EXPANDING SO YOU SHOULD PROBABLY STOP PUTTING THINGS IN YOUR MOUTH!”

Unfortunately for us, although the leptin signal tells us we are full, it is not strong enough to actually stop us from stuffing ourselves.

In addition to leptin, adipocytes release (secrete) a bunch of other molecules that have various activities in the body. One of these is a protein called adiponectin – it increases insulin sensitivity, reduces inflammation, prevents cells from dying (apoptosis), and promotes the growth of blood vessels (angiogenesis). The main function of this protein is to give adipose tissue flexibility in releasing free fatty acids when the body needs them, and in improving the efficiency of turning free fatty acids into triacylglycerol after a meal. Other molecules secreted by adipocytes include cell signaling molecules that encourage inflammation (proinflammatory cytokines) and components of the matrix outside of the cells (extracellular matrix).

Becoming Obese is a Defense Mechanism Against Metabolic Syndrome

Insulin increases the creation of fat from blood sugar (lipogenesis) and this fat is almost exclusively stored in adipose tissue, leading to obesity. The authors argue that the creation of fat cells for increased fat storage capability (adipogenesis, or fat pad expansion) delays rather than causes metabolic syndrome, and that this shows that obesity cannot and should not be associated with metabolic syndrome.

Healthy fat pad expansion is dependent on many different factors, including gender, genes, and the amount of fibrous proteins in fat tissue. A healthy fat pad has a large number of small fat cells (as opposed to a few huge ones), has healthy blood vessels, and is not inflammed. Location of fat is important as well; fat under the skin (subcutaneous) can have a good effect on insulin sensitivity, whereas fat around organs is unhealthy. Females tend to be more protected against insulin resistance than males. In one genetic mouse model called ob/ob, which produces a higher than normal amount of adiponectin, the mice had ‘expansion of the adipocyte compartment’ (ie they got really fat) and this protected them against developing certain features of metabolic syndrome. Evidence points to the fact that our ability to increase the size of our fat pads productively is protective.

The authors wanted to test if the opposite is true – if preventing obesity makes metabolic syndrome worse. They used two different transgenic mouse strains (this means that the mice had a genetic mutation/change that made them different from regular ol’ mice). The aP2-lepr-b mouse has a genetic mutation that makes it resistant to becoming obese. The db/db mouse has a genetic mutation that causes them to over-eat, become obese, and as they grow up they develop metabolic syndrome and type 2 diabetes. The authors mated the two types of mice together to create a new mutant mouse that has both sets of characteristics – it over-eats but is resistant to becoming obese. These new mice never become obese, but they develop severe diabetes… and it develops a full month earlier than it would in the obese db/db mice. The insulin-producing beta-cells in their pancreases were completely obliterated at an age where the db/db mice still had healthy pancreases. This showed that when adipocytes do not have the capacity to store the extra fat from over eating, this fat gets deposited elsewhere, leading to severe problems and the development of metabolic syndrome and diabetes.

The take home message for humans is that obesity is a normal response to consuming more calories than necessary. The metabolic syndrome develops only after the fat cells have been filled to the maximum, and fatty acids have no where to go, so they spill over and settle on cells that are not designed to deal with them (called ectopic lipid accumulation).

Leptin Resistance – Never Knowing When You’re Full

We learned from earlier than leptin is a heroic hormone that makes sure stray fatty acids are oxidized rather than allowed to land all over your organs, and also lets your brain know when you’re full. Leptin resistance is a major player in metabolic syndrome because it prevents leptin from doing its critical job, leading to fatty acids floating around all over the place and weakening the “I’m Full!” signal, leaving your brain hungry while your stomach if filled to the brim. The mechanisms behind leptin resistance are not known, but scientists think that there might be a problem with leptin making it to the brain.

Insulin Resistance – Another Protective Mechanism?

Resistance to insulin is usually thought of a direct cause of obesity, metabolic syndrome, and other related diseases. However, there is some evidence that shows that insulin resistance in obesity is secondary to fats incorrectly accumulating in the liver and skeletal muscles (ie not organs). Insulin resistance is also limited to insulin’s role in glucose metabolism (controlling levels of sugar in the blood), but insulin is not affected when it comes to lipogenesis (creation of fat), and this proceeds at a high rate. Since insulin’s target tissues (liver and muscles) are being bombarded with fat to store, scientists think these tissues might reject glucose carried by insulin (showing insulin resistance) to protect themselves from collecting any more fuel that could be later turned into fat (glucose can be turned into fat). The authors argue that insulin resistance is not a cause of metabolic syndrome, but is a protective mechanism for the liver and muscles.

Read Part I Read Part III